Cutaneous malignant melanoma is the deadliest form of skin cancer. Ultraviolet radiation (UVR) in sunlight plays a causative role in melanoma development both as an initiator, through mutational activation of oncogenes such as BRAF, and as a promoter through effects on melanocyte migration and proliferation. While intense UVR resulting in sunburns is associated with melanoma risk, epidemiology shows that persistent lower level chronic exposure may protect against melanoma. This proposal focuses on the transcription factor p53, a sensor of genomic and cellular stress, and its action in keratinocytes after UVR. UVR activates p53 in keratinocytes, and depending on the level or type of damage, induces keratinocyte apoptosis (sunburn cells), and increases the expression of melanocyte growth factors, like KIT Ligand (KITLG), that control melanocyte proliferation and function; therefore p53 may well modulate melanoma risk. Indeed, in our Sooty Foot Ataxia (SFA) mice with constitutively high p53 levels in keratinocytes, we observed increased expression of keratinocyte-derived melanocyte growth factors and elevated melanocyte numbers. Importantly, these mice develop nevi and melanomas when subjected to a carcinogenesis protocol. These data strongly suggest a tumor promotional role for keratinocyte p53. Recently, we identified a key human cancer risk SNP in the p53 transactivation site at the KITLG locus that resulted in increased KITLG expression post-UVR. Together these data led us to hypothesize that strong p53 activation in keratinocytes stimulates a growth factor-rich environment that promotes the initiation and progression of pigmented lesions to melanoma; whereas persistent low p53 activation protects against melanoma development. This new role for p53 will be tested using both our constitutive keratinocyte p53 overexpressing SFA mice and our Doxycycline-inducible Tet-ON keratinocyte p53 overexpressing mice. In Aim 1, we will examine the impact of p53 activation in keratinocytes on the release of paracrine factors and on melanocyte proliferation. A detailed analysis of p53 pathway activity, including regulators and target genes, in the presence of different levels of p53 will allow us to construct a model of p53 action in keratinocytes that may explain the apparent link between acute intense UVR and melanoma risk and the association of chronic low UVR with protection from melanoma. In Aim 2, we will use our Tet-ON p53 mice in combination with the BrafV600E melanoma mouse model to study the paracrine effects of different levels of p53 activation in keratinocytes on nevus and melanoma development. We will investigate both acute intense p53 activation as a melanoma promoter, and low chronic p53 activation as a mediator of protection against UVR-induced melanoma. This proposal will yield a greater understanding of p53 signaling in keratinocytes and its impact on melanocytes and melanoma that may ultimately lead to new strategies for melanoma chemoprevention. The data generated in this proposal will be used to support an R01 application investigating these strategies.